Lung cancer continues to be the leading cause of cancer death in the United States, with relatively minimal improvements in survival over the last several decades. Within the last few years, the identification of driver mutations and genetic alterations has led to successes in outcomes using targeted treatment. The frequency of these alterations may vary in specific patient populations, such as never smokers, Asians, women, and specifically in histologic subtypes of NSCLC. However, there have been no large studies of the genetic alterations in lung tumors from African Americans. Our preliminary data suggest variability in the mutation rates among African American patients. We propose to conduct a comprehensive analysis of genetic alterations in a large sample of African American lung cancer patients using a screening panel of known oncogenic mutations and alterations, followed by whole exome sequencing in those samples with no known mutations. The specific aims of the proposed study are to: 1) Identify mutations in NSCLC samples from 200 African Americans using a lung cancer panel that includes 214 somatic mutations in 26 genes frequently mutated in NSCLC. 2) Identify genetic alterations in those tumor samples from African Americans whose tumors show no mutations on the lung cancer panel using whole exome sequencing. Whole exome sequencing will be conducted in both tumor and normal DNA from the estimated 100 to 120 African American lung cancer cases whose tumors do not carry a known mutation. 3) Characterize genetic alterations in lung tumors from African Americans in terms of smoking, sex, histology, stage and age at diagnosis. Recurrence and overall survival will be evaluated for specific alterations and by number of mutations or alterations with a frequency of greater than 5%. This will be the largest study to profile NSCLCs in African Americans and includes using whole exome sequencing to characterize genetic alterations in known genes and to identify rare variants. The focus on the African American population will provide complementary information to studies in whites and Asians, and is particularly powerful because of the diversity in genetic architecture and lower exposures to tobacco smoking in this population. The proposed study has the potential to identify novel treatment targets leading to a reduction in the racial disparites in lung cancer survival and an improvement in survival for all lung cancer patients.